Therapeutic targeting of DNA methylation alterations in cancer.

DNA methylation is a critical component of gene regulation and plays an important role in the development of cancer. Hypermethylation of tumor suppressor genes and silencing of DNA repair pathways facilitate uncontrolled cell growth and synergize with oncogenic mutations to perpetuate cancer phenotypes. Additionally, aberrant DNA methylation hinders immune responses crucial for antitumor immunity. Thus, inhibiting dysregulated DNA methylation is a promising cancer therapy. Pharmacologic inhibition of DNA methylation reactivates silenced tumor suppressors and bolster immune responses through induction of viral mimicry. Now, with the advent of immunotherapies and discovery of the immune-modulatory effects of DNA methylation inhibitors, there is great interest in understanding how targeting DNA methylation in combination with other therapies can enhance antitumor immunity. Here, we describe the role of aberrant DNA methylation in cancer and mechanisms by which it promotes tumorigenesis and modulates immune responses. Finally, we review the initial discoveries and ongoing efforts to target DNA methylation as a cancer therapeutic.

Findings from the Promoting Independence in Dementia App (PRIDE-app) Study a Reach, Effectiveness, Adoption, Implementation, and Maintenance Framework Discussion.

INTRODUCTION: Self-management is pivotal in helping people with their independence and in managing their health conditions more effectively. The PRIDE-app is a novel online intervention, providing support and information for people living with dementia and their families, aimed at increasing self-management and improving quality of life. Knowledge generated will help inform future developments to the app, with the aim of improving its uptake and implementation in services. METHODS: A mixed-methods approach incorporating the RE-AIM framework. Recruited 25 people living with dementia, of which 17completed the PRIDE-app intervention over 8 weeks with support from a dementia adviser facilitator. Measures exploring mood, physical well-being, and quality of life were collected at baseline, 3 and 6 months and analysed through modelled analysis. Post-intervention interviews were conducted with participants and facilitators and analysed through thematic analysis. RESULTS: Quantitative results did not show significant improvements in participants' scores. Qualitative data showed that the PRIDE-app motivated people to reconnect socially and set individual goals for activities. Participants and facilitators identified areas for improvements to the app interface and delivery format. CONCLUSIONS: This study evaluated the PRIDE-app's reach, effectiveness and adoptability in the independence and quality of life of people living with dementia, as well as how it could be implemented and maintained within services. Pre- and post-intervention scores were inconclusive. Interviews provided positive feedback of the app's influence on peoples' activities and mood.

Physician factors affecting patient preferences in selecting a primary care provider: A qualitative research study in Singapore.

BACKGROUND: Care continuity by a dedicated, well-trained primary care physician (PCP) has shown to improve health outcomes of patients with non-communicable diseases (NCDs). In Singapore's fee-for-service primary care system, patients can choose to consult any PCP in either a public (polyclinic), private (General Practitioners/ GP), or both types of clinics, resulting in potential fragmented care. Decision-making by patients in selecting their preferred PCP remains unclear. This study aims to explore the personal factors influencing the choice of PCP among patients with NCDs in primary care. METHODS: This qualitative research study was conducted in a typical polyclinic. In-depth interviews were conducted on patients with NCDs. Purposive sampling was implemented to enrol patients who had previously consulted PCPs in polyclinics and GP clinics, garnering their perspectives and experiences of care received from both providers. Interviews were audio-recorded, transcribed, and audited. Data was coded and analysed using thematic content analysis to identify emerging themes. The physician-specific factors which influence patients' decision-making of PCP selection are presented here. RESULTS: Twenty-one Asian patients aged 38 to 82 years were interviewed. They preferred PCPs with an approachable and genuine demeanour, exhibiting empathy and compassion. They valued the PCPs' verbal, non-verbal and listening skills. Regarding professional qualities, patients wanted PCPs to demonstrate competency and a patient-centred care approach. Some selected their PCP based on compatible age and gender that they felt comfortable with. Establishing good rapport with their PCP and maintaining continuity of care were deemed as major factors in patients' PCP selection. CONCLUSION: Patients tended to select PCPs based on their personal characteristics, interpersonal skills, professional attributes, demographics, and the physician-patient relationship. PCPs should be aware of these attributes and demonstrate them during their patient interaction. Leveraging on this enables PCPs to build rapport with their patients and maintain care continuity to optimize their health outcomes.

Online peer support for people with Amyotrophic Lateral Sclerosis (ALS): a narrative synthesis systematic review.

Background: Amyotrophic Lateral Sclerosis (ALS) significantly impacts the lives of people with the diagnosis and their families. A supportive social environment is important for people with ALS to adopt effective coping strategies and health behaviours, and reduce depressive symptoms. Peer support can provide a supportive social environment and can happen in-person and online. Advantages of online peer support are that people can engage from their own home, at their own time and pace, and that it offers a variety of different platforms and modes of communication. Objectives: To (1) explore the benefits and challenges of online peer support for people with ALS, and (2) identify successful elements of online peer support for people with ALS. Methods: The method selected for this systematic review was a narrative synthesis. Six databases were systematically searched in April 2020 for articles published between 1989 and 2020. The search was updated in June 2022. The quality of the included studies was assessed with the Critical Appraisal Skills Programme qualitative research checklist. Results: 10,987 unique articles were identified through the systematic database search. Of those, 9 were included in this review. One of the main benefits of online peer support was that people could communicate using text rather than needing verbal communication, which can be challenging for some with ALS. Successful elements included using profile pages and graphics to identify others with similar or relevant experiences. Challenges included ALS symptoms which could make it difficult to use technological devices. Conclusions: Peer support can provide a non-judgmental and supportive environment for people with ALS, in which they can exchange experiences and emotional support, which can help people in developing adaptive coping strategies. However, ALS symptoms may make it more difficult for people to use technological devices and engage in online peer support. More research is needed to identify what kind of specific barriers people with ALS experience, and how these could be overcome.

Perceiving depth and motion in depth from successive occlusion.

Occlusion, or interposition, is one of the strongest and best-known pictorial cues to depth. Furthermore, the successive occlusions of previous objects by newly presented objects produces an impression of increasing depth. Although the perceived motion associated with this illusion has been studied, the depth percept has not. To investigate, participants were presented with two piles of disks with one always static and the other either a static pile or a stacking pile where a new disk was added every 200 ms. We found static piles with equal number of disks appeared equal in height. In contrast, the successive presentation of disks in the stacking condition appeared to enhance the perceived height of the stack-fewer disks were needed to match the static pile. Surprisingly, participants were also more precise when comparing stacking versus static piles of disks. Reversing the stacking by removing rather than adding disks reversed the bias and degraded precision. In follow-up experiments, we used nonoverlapping static and dynamic configurations to show that the effects are not due to simple differences in perceived numerosity. In sum, our results show that successive occlusions generate a greater sense of height than occlusion alone, and we posit that dynamic occlusion may be an underappreciated source of depth information.

Decrease in Overall Vaccine Hesitancy in College Students during the COVID-19 Pandemic.

The COVID-19 pandemic changed our world as we know it and continues to be a global problem three years since the pandemic began. Several vaccines were produced, but there was a considerable amount of societal turmoil surrounding them that has affected the way people view not only COVID-19 vaccines but all vaccines. We used a survey to compare how attitudes towards vaccination have changed in college students during the pandemic. An initial survey was administered in 2021, then a follow-up in 2022. Out of 316 respondents who answered the first survey, 192 completed the follow-up. The survey was designed to measure trends in changes to vaccine attitudes since the COVID-19 pandemic began. By comparing the first survey in 2021 and the follow-up, we found that roughly 55% of respondents' vaccine attitudes did not change, roughly 44% of respondents' attitudes towards vaccines became more positive, and only about 1% of the respondents' vaccine attitudes became more negative. Improved view of vaccines was associated with political views and increased trust in medicine and the healthcare system. Worsened opinions of vaccines were associated with a belief that the COVID-19 vaccine affected fertility.

Factors Affecting Vaccine Attitudes Influenced by the COVID-19 Pandemic.

The development of vaccines has significantly contributed to the success of disease prevention. However, there has been a sharp decline in immunization rates since COVID-19 spread globally. Seemingly overnight, the world shut down and most non-essential medical procedures were postponed. Since the COVID-19 vaccine became available, and the world started going back to normal these vaccine rates have not recovered. In this paper, we review the published literature to explore how convenience factors, perceived risk of vaccination, media or anti-vaccination ideals/movements, and healthcare professionals affect an individual's compliance to be vaccinated to better understand the factors that contribute to the change in overall vaccination rates.

Sex-disease dimorphism underpins enhanced motion sickness susceptibility in primary adrenal insufficiency: a cross-sectional observational study.

Environmental motion can induce physiological stress and trigger motion sickness. In these situations, lower-than-normal levels of adrenocorticotropic hormone (ACTH) have been linked with increased susceptibility to motion sickness in healthy individuals. However, whether patients with primary adrenal insufficiency, who typically have altered ACTH levels compared to the normal population, exhibit alterations in sickness susceptibility remains unknown. To address this, we recruited 78 patients with primary adrenal insufficiency and compared changes in the motion sickness susceptibility scores from 10 years prior to diagnosis (i.e. retrospective sickness rating) with the current sickness measures (post-diagnosis), using the validated motion sickness susceptibility questionnaire (MSSQ). Group analysis revealed that motion sickness susceptibility pre-diagnosis did not differ between controls and patients. We observed that following treatment, current measures of motion sickness were significantly increased in patients and subsequent analysis revealed that this increase was primarily in female patients with primary adrenal insufficiency. These observations corroborate the role of stress hormones in modulating sickness susceptibility and support the notion of a sexually dimorphic adrenal cortex as we only observed selective enhancement in females. A potential mechanism to account for our novel observation remains obscure, but we speculate that it may reflect a complex sex-disease-drug interaction.

A Web-Based Self-management App for Living Well With Dementia: User-Centered Development Study.

BACKGROUND: Self-management, autonomy, and quality of life are key constructs in enabling people to live well with dementia. This population often becomes isolated following diagnosis, but it is important for them to feel encouraged to maintain their daily activities and stay socially active. Promoting Independence in Dementia (PRIDE) fosters social inclusion and greater dementia self-management through an interactive handbook. OBJECTIVE: This study aimed to develop a paper-based PRIDE manual on a web-based platform. METHODS: Two overarching stages were used to create the web-based version of PRIDE. The first was Preliminary Development, which encompassed tendering, preliminary development work, consultations, beta version of the website, user testing and consultation on beta version, and production of the final web-based prototype. The second stage was Development of the Final PRIDE App, which included 2 sprints and further user testing. RESULTS: Through a lengthy development process, modifications were made to app areas such as the log-in process, content layout, and aesthetic appearance. Feedback from the target population was incorporated into the process to achieve a dementia-friendly product. The finished PRIDE app has defined areas for reading dementia-related topics, creating activity plans, and logging these completed activities. CONCLUSIONS: The PRIDE app has evolved from its initial prototype into a more dementia-friendly and usable program that is suitable for further testing. The finished version will be tested in a reach, effectiveness, adoption, implementation, and maintenance study, with its potential reach, effectiveness, and adoption explored. Feedback gathered during the reach, effectiveness, adoption, implementation, and maintenance study will lead to any further developments in the app to increase its applicability to the target audience and usability.

Understanding Barriers and Facilitators to Online and App Activities for People Living With Dementia and Their Supporters.

BACKGROUND: Stigma often surrounds people with dementia when it comes to use of computer technology, although evidence does not always support this. More understanding is needed to investigate attitudes and experience in relation to computer technology use among those living with dementia and their readiness to use it to support self-management. METHODS: An online self-report questionnaire was completed by adults living with a dementia diagnosis and those living with them. Questions explored how long the participants had been using computer technology; how regularly they used it; the popularity of common communication apps; and whether they were interested in using an app to support their independence. RESULTS: 47 participants with dementia and 62 supporters responded to the questionnaire. There were no obvious differences between those with dementia and supporters when it came to regular technology usage and both groups showed positive attitudes to the use of it for independence in dementia. CONCLUSIONS: There was active use of computer technology among this population. Benefits were shown to include communication, increasing individuals' understanding of dementia diagnoses, and enabling independent activities for both those with dementia and supporters.

Online Peer Support for People With Multiple Sclerosis: A Narrative Synthesis Systematic Review.

BACKGROUND: People with multiple sclerosis often experience depression and anxiety, negatively affecting their quality of life, especially their social life. Peer support, whether in person or online, could improve social connection and coping. Online peer support allows people to engage from their home at a time that suits them. We sought to explore the benefits and challenges of online peer support and to identify successful elements of online peer support for people with multiple sclerosis. METHODS: Using the narrative synthesis method, 6 databases were searched in April 2020 for articles published between 1989 and 2020; the search was updated in May 2022. The quality of the included studies was assessed using the Critical Appraisal Skills Programme qualitative research checklist and the Downs and Black checklist. RESULTS: Of 10,987 unique articles identified through the database search, 11 were included. Benefits of online peer support included sharing information and experiences and emotional support. Successful elements included having a dedicated space to save information and the convenience of online peer support. Challenges included verification of information and the lack of nonverbal communication. CONCLUSIONS: Online peer support can help those unable to access in-person support groups and can reduce the risk of social isolation. However, multiple sclerosis symptoms may make it difficult to use technological devices. Research is needed to further explore potential barriers to online peer support.

Cautious Sexual Attitudes Diminish Intent to Vaccinate Children against HPV in Utah.

Although most Human papillomavirus (HPV) infections are mild and are cleared by the immune system, some high-risk HPV strains can cause various cancers. Vaccines have been developed that protect against high-risk HPV strains. HPV vaccines have been approved for use by the CDC (Centers for Disease Control and Prevention) and are recommended for everyone aged 11-26. Despite the availability of safe and effective vaccines, uptake is low. HPV vaccine uptake has been extensively studied on a national and international level, but less is known about vaccine acceptance on a state or local level. The state of Utah, in the United States of America, has a relatively low HPV vaccination rate. In this study, we identified factors that impact the intent of Utah parents to vaccinate their children against HPV. A survey was distributed electronically to Utah residents. Survey results were analyzed using confirmatory factor analysis, structural equation modeling, and univariate analysis. Knowledge about HPV and positive vaccine attitudes had the greatest positive effect on intent to vaccinate children against HPV. Cautious sexual attitudes and high religious practice were found to have a negative impact on intent to vaccinate. Effective public health messaging will consider the cultural and religious influences of the target population.

Online Peer Support for People With Parkinson Disease: Narrative Synthesis Systematic Review.

BACKGROUND: Parkinson disease (PD) significantly impacts the lives of people with the diagnosis and their families. In addition to the physical symptoms, living with PD also has an emotional impact. This can result in withdrawal from social roles, increasing the risk for social isolation and loneliness. Peer support is a way to stay socially connected, share experiences, and learn new coping skills. Peer support can be provided both in person and on the internet. Some of the advantages of online peer support are that it overcomes geographical barriers and provides a form of anonymity; moreover, support can be readily available when needed. However, the psychosocial impact of PD is still underresearched, and there is no systematic synthesis of online peer support for people with PD. OBJECTIVE: This review aims to explore the benefits and challenges of online peer support and identify successful elements of online peer support for people with PD. METHODS: The method selected for this systematic review is narrative synthesis. A total of 6 databases were systematically searched in April 2020 for articles published between 1989 and 2020. The quality of the included studies was assessed using the Critical Appraisal Skills Programme qualitative research checklist and the Downs and Black quality checklist. RESULTS: A total of 10,987 unique articles were identified through a systematic database search. Of these 10,987 articles, 8 (0.07%) were included in this review. Of the 8 studies, 5 (63%) were of good or high quality, 2 (25%) were of medium or fair quality, and 1 (13%) study was of poor quality. Web-based platforms included discussion forums, a web-based virtual world, and Facebook groups. Most papers reported on text-based communication. The included studies reported on sharing social support and personal experiences. Successful elements included increasing similarity between members and offering the opportunity to directly ask questions to a physician. Challenges included members leaving without a warning and PD symptoms hindering the use of technology. CONCLUSIONS: Peer support can improve social support and help people with PD in living meaningful and satisfying lives. Peer support is unique and cannot be replaced by family members, friends, or health care professionals. Online peer support can be a solution for those who do not have access to an in-person support group or whose PD symptoms restrict them from travelling. However, research on the personal experiences of those who engage in online peer support and potential barriers in accessing it remains limited. Future research could use qualitative methods to explore these fields further.

A Self-management App for People Living With Mild Dementia (PRIDE): Protocol for a Pre-Post Feasibility Study.

BACKGROUND: With the rapid increase in the prevalence of dementia in the United Kingdom and beyond, the emotional, social, and economic burden on individuals, families, and health care services continues to rise. Currently, interventions that enable people living with dementia to better manage their condition and achieve a good quality of life are needed. OBJECTIVE: This study aimed to explore how the Promoting Independence in Dementia (PRIDE) app can promote and support the self-management of people living with mild dementia. METHODS: Feasibility of a pre-post study design incorporating the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework will be studied. We will use up to 6 National Health Service Trusts as research sites and the Join Dementia Research website and accept self-referrals to recruit 60 to 90 people living with mild dementia. Participants will complete the PRIDE app intervention over 8 weeks with support from a dementia adviser facilitator. Measures exploring mood, physical well-being, and quality of life will be collected at baseline and at follow-ups at 3 and 6 months. Facilitators and National Health Service staff will be invited to complete interviews shortly after the intervention phase. RESULTS: Data collection began in June 2021 and is predicted to cease by the end of August 2022. Analysis of the quantitative measures will explore the impact of the PRIDE app on participants' independence, mood, and quality of life. Interview data will discuss participant experiences, how the use of the app affected them, and if it has the potential to be successfully implemented and maintained in dementia services. CONCLUSIONS: This study will show the potential reach, effectiveness, and adoption of the PRIDE app intervention in the lives of people with mild dementia. The findings from this study will inform future research on the PRIDE app and any further developments to improve its effectiveness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/33881.

Concise Reporting of Benign Endometrial Biopsies is an Acceptable Alternative to Descriptive Reporting.

In the United Kingdom, endometrial biopsy reports traditionally consist of a morphologic description followed by a conclusion. Recently published consensus guidelines for reporting benign endometrial biopsies advocate the use of standardized terminology. In this project we aimed to assess the acceptability and benefits of this simplified "diagnosis only" format for reporting non-neoplastic endometrial biopsies. Two consultants reported consecutive endometrial biopsies using 1 of 3 possible formats: (i) diagnosis only, (ii) diagnosis plus an accompanying comment, and (iii) the traditional descriptive format. Service users were asked to provide feedback on this approach via an anonymized online survey. The reproducibility of this system was assessed on a set of 53 endometrial biopsies among consultants and senior histopathology trainees. Of 370 consecutive benign endometrial biopsies, 245 (66%) were reported as diagnosis only, 101 (27%) as diagnosis plus a brief comment, and 24 (7%) as diagnosis following a morphologic description. Of the 43 survey respondents (28 gynecologists, 11 pathologists, and 4 clinical nurse specialists), 40 (93%) preferred a diagnosis only, with 3 (7%) being against/uncertain about a diagnosis only report. Among 3 histopathology consultants and 4 senior trainees there was majority agreement on the reporting format in 53/53 (100%) and 52/53 (98%) biopsies. In summary, we found that reporting benign specimens within standardized, well-understood diagnostic categories is an acceptable alternative to traditional descriptive reporting, with the latter reserved for the minority of cases that do not fit into specific categories. This revised approach has the potential to improve reporting uniformity and reproducibility.

Exenatide-induced granulomatous panniculitis associated with poly(d,l-lactide-co-glycolide).

The extended-release formulation of exenatide for treatment of Type II diabetes mellitus is encapsulated in microspheres composed of poly(d,l-lactide-co-glycolide) (PLGA) and administered weekly. This medication has been reported to potentially cause injection-site reactions such as pruritus, transient nodules, and foreign body reaction. Here, we report a case of exenatide-induced granulomatous panniculitis. Our patient is a 63-year-old female with Type II diabetes presenting for concerns about painful nodules on her abdomen, developing approximately every week over the past year and migrating. Of note, the lesions appeared following exenatide injections in the same locations. Two deep-seated nodules of 1 cm were identified on examination. There were no overlying skin changes, and the lesions were tender to palpation. Punch biopsies of the two lesions were performed, which revealed a septal panniculitis containing amorphous material, along with a mixed inflammatory infiltrate. Gomori methenamine silver (GMS) and acid-fast bacilli (AFB) stains were negative for organisms. On infrared (IR) spectroscopy examination of the biopsy tissue, the spectral characteristics of (tissue) protein and PLGA were seen. Evaluation of the clinical and histopathologic findings, along with the IR spectroscopy match, determined that exenatide-induced panniculitis was the cause of the patient's nodules. This case highlights the importance of clinicians' awareness regarding injection-site reactions.

Exploring the Role of Web-Based Interventions in the Self-management of Dementia: Systematic Review and Narrative Synthesis.

BACKGROUND: The increasing prevalence of dementia has promoted a move toward equipping people with the skills required for greater self-management of the condition to enable a better quality of life. Self-management encompasses numerous skills, such as goal setting and decision making, which aim to improve an individual's physical and mental well-being when they live with long-term health conditions. Effective self-management may lead to increased well-being and quality of life. Reviews of web-based and app-based interventions have suggested that they have the potential to provide self-management support for people living with a range of conditions, including dementia. OBJECTIVE: The aim of this review is to explore the existing use of web-based or app-based interventions that facilitate or support self-management in dementia and discuss their effectiveness in promoting self-management and independence. METHODS: A total of 5 electronic databases were systematically searched for relevant articles published between January 2010 and March 2020. Included studies were appraised using the Downs and Black checklist and the Critical Appraisal Skills Program qualitative research checklist. A narrative synthesis framework was applied using tables and conceptual mapping to explore the relationships within and among studies. RESULTS: A total of 2561 articles were identified from the initial search, of which 11 (0.43%) met the inclusion criteria for the final analysis. These included 5 quantitative, 4 mixed methods, and 2 qualitative studies. All the included articles were of fair to high quality across the two appraisal measures. Interventions were delivered through a range of web-based and app-based technologies and targeted several self-management concepts. However, there was inconsistency regarding the domains, often affected by dementia, that were targeted by the interventions reviewed. CONCLUSIONS: Web-based and app-based interventions for dementia can be delivered through a range of means and can target different aspects of self-management. The small number of studies included in this review report positive outcomes that seem to support the use of these interventions for people living with dementia. However, there is a clear need for more high-quality research into this type of intervention delivery and for studies that use a much larger number of participants across the dementia spectrum. Future research should consider the barriers to and facilitators of intervention adoption highlighted in this review and whether interventions can encompass the physical, social, cognitive, and emotional domains affected by dementia.

Extreme Acid Modulates Fitness Trade-Offs of Multidrug Efflux Pumps MdtEF-TolC and AcrAB-TolC in Escherichia coli K-12.

Bacterial genomes encode various multidrug efflux pumps (MDR) whose specific conditions for fitness advantage are unknown. We show that the efflux pump MdtEF-TolC, in Escherichia coli, confers a fitness advantage during exposure to extreme acid (pH 2). Our flow cytometry method revealed pH-dependent fitness trade-offs between bile acids (a major pump substrate) and salicylic acid, a membrane-permeant aromatic acid that induces a drug resistance regulon but depletes proton motive force (PMF). The PMF drives MdtEF-TolC and related pumps such as AcrAB-TolC. Deletion of mdtE (with loss of the pump MdtEF-TolC) increased the strain's relative fitness during growth with or without salicylate or bile acids. However, when the growth cycle included a 2-h incubation at pH 2 (below the pH growth range), MdtEF-TolC conferred a fitness advantage. The fitness advantage required bile salts but was decreased by the presence of salicylate, whose uptake is amplified by acid. For comparison, AcrAB-TolC, the primary efflux pump for bile acids, conferred a PMF-dependent fitness advantage with or without acid exposure in the growth cycle. A different MDR pump, EmrAB-TolC, conferred no selective benefit during growth in the presence of bile acids. Without bile acids, all three MDR pumps incurred a large fitness cost with salicylate when exposed at pH 2. These results are consistent with the increased uptake of salicylate at low pH. Overall, we showed that MdtEF-TolC is an MDR pump adapted for transient extreme-acid exposure and that low pH amplifies the salicylate-dependent fitness cost for drug pumps. IMPORTANCE Antibiotics and other drugs that reach the gut must pass through stomach acid. However, little is known of how extreme acid modulates the effect of drugs on gut bacteria. We find that extreme-acid exposure leads to a fitness advantage for a multidrug pump that otherwise incurs a fitness cost. At the same time, extreme acid amplifies the effect of salicylate selection against multidrug pumps. Thus, organic acids and stomach acid could play important roles in regulating multidrug resistance in the gut microbiome. Our flow cytometry assay provides a way to measure the fitness effects of extreme-acid exposure to various membrane-soluble organic acids, including plant-derived nutrients and pharmaceutical agents. Therapeutic acids might be devised to control the prevalence of multidrug pumps in environmental and host-associated habitats.

DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life.

Synthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.